Preparation of androstadiene propionic acid lactone and intermediates thereof



United States Patent 3,413,289 PREPARATION OF ANDROSTADIENE PRO- PIONICACID LACTONE AND INTERME- DIATES THEREOF George Gal, Summit, and MeyerSletzinger, North Plainfield, N.J., assignors to Merck & Co., Inc.,Rahway, N.J., a corporation of New Jersey N0 Drawing. Filed Apr. 21,1966, Ser. No. 544,077 8 Claims. (Cl. 260-23957) ABSTRACT OF THEDISCLOSURE The invention disclosed herein is generally concerned withthe preparation of 3-(4,6-androstadien-17fi-ol-3-on 17u-yl)-propionicacid lactone and to intermediate steroids which are useful in thepreparation thereof. This lactone is prepared b reacting3;8-hydroxy-5,6-dibromo- 20-spiroxane with N-bromosuccinimide, anddehydrobrominating the resulting 5,6- dibromoandrostane compound. 3 (4,6androstadien-17fi-ol-3-one-l7a-yl)-propionic acid lactone possessesuseful therapeutic properties as an aldosterone inhibitor. Aldosteroneinhibitors block the salt-retaining effects of aldosterone and othersaltretaining steroids and thereby have utility in the treatment ofdiseases such as congestive heart failure, nephrosis, and cirrhosis ofthe kidney in which aldosterone secretion is increased.

More particularly this invention relates to3-(5,6-dibromoandrostane-17fl-o1-3-one-17a-yl)-propionic acid lactoneand a method for the preparation thereof and to a method for thepreparation of 3-(4,6-androstadien-17B- ol-3-one-l7a-yl)-propionic acidlactone.

The starting material for the preparation of the novel intermediatesteroid compounds of this invention is3fi-hydroxy-5,6-dibromo-ZO-spiroxane. The starting compound may beconveniently prepared by a series of reaction steps starting With afirst step of reacting dehydroepiandrosterone tetrahydropyranyl etherwith 3-lithiopropanyl-1,2-tetrahydropyranyl ether to provide 17a-(3'-hydroxypropyl)-5-androstene-313,l7}9 diol di-tetrahydropyranyl ether.This reaction is accomplished by adding an ether solution of3-lithiopropanyl-1,2'-tetrahydropyranyl ether to a solution ofdehydroepiandrosterone tetrahydropyranyl ether in an anhydrous organicsolvent, preferably tetrahydrofuramthe temperature of the reactionmixture being kept below about 30 C. during the addition. After additionis complete, the reaction mixture is allowed to stand at roomtemperature for about hours. The reaction mixture is then added toWater, and the reaction product is removed by extraction with a suitableorganic solvent, such as ether. The ether extract is washed with water,dried, and the solvent is removed by distillation under reducedpressure. The residue is 17a-(3-hydroxypropyl) 5 androstene-3B,l7B-dioldi-tetrahydropyranyl ether. The latter compound is converted in thesecond step to 17fi-(3'-hydroxypropyl)-5-androstene- 33,17B-diol withoutpurification by allowing a solution thereof in a suitable solvent, suchas ethanol, containing catalytical amount of strong acid, preferablyp-toluenesulfonic acid to stand at room temperature for several hours.17a-(3'-hydroxypr0pyl)-5-andr0stene-3B,17,8-diol precipitates from thereaction mixture on standing and is filtered off, washed with a suitablesolvent, such as ethanol, and dried under reduced pressure. In the thirdstep, l7a-(3-hydroxypropyl)-5-androstene-3B,l7B-diol is treated inpyridine solution with an acid chloride of an aromatic or aliphaticsulfonic acid, such as p-toluenesulfonyl chloride ormethanesulfonylchloride, to provide a 3f3-aromaticsulfonyloxy--spirox-5-ene or a 3 8-aliphatic sulfonyloxy-20- BestAVAILABLE coat Patented Nov. 26, 1968 ice spirox-S-ene, such as3B-p-toluenesulfonyloxy-20-spirox- S-ene or3/3-mesyloxy-20-spirox-S-ene. The latter compound is converted in thefourth step to 3B-hydroxy-20- spirox-S-ene. The third step reaction maybe conveniently accomplished by adding the aromatic or aliphaticsulfonyl chloride dropwise to a slurry of l7a-(3'-hydroxypropyl)-5-androstene-3;8,17B-diol in anhydrous pyridine. During theaddition the reaction mixture is maintained at a temperature of about 10C., and the acid chloride is added over a period of from about 20 to 30minutes. After addition is complete, the mixture is stirred for about 3hours at a temperature in the range from about 10 C. to 0' C. and thenallowed to stand overnight at room temperature. The reaction product isisolated by pouring the reaction mixture into ice water and removing theprecipi tated product by extraction with a siutable solvent, such asethyl acetate. The extract is washed with cold dilute hydrochloric aciduntil it is free from pyridine, and the solvent is removed from theresulting solution by distillation under reduced pressure. The residueis crude 3/8- aromatic sulfonyloxy-20-spirox-S-ene or Bit-aliphaticsulfonyloxy-ZO-spirox-S-ene and may be used without purification in thefourth step to produce 3B-hydroxy-20-spirox- S-ene. This is convenientlyaccomplished by dissolving the crude material in aqueous acetone,preferably in a 4.5-1 acetone-water solvent mixture and heating theresulting solution under reflux for several hours. The reaction productmay be isolated by removing the acetone by distillation under reducedpressure and simultaneously adding water to maintain a constant volume.3B-hydroxy-20- spirox-S-ene precipitates as acetone is removed. Afterall of the acetone is removed, the resulting slurry is cooled to about10 C. and the solid material is removed by filtration and dried underreduced pressure. The crude 3fi-hydroxy-20-spirox-5-ene may be purifiedby suspending in a suitable organic solvent, such as normal-hexane, and

stirring the resutling slurry at a temperature of about 60 C. forseveral hours, cooling the mixture to room temperature, filtering,washing the solid material with a suitable solvent, such asnormal-hexane, and drying the solid material under reduced pressure. Inthe fifth step, SB-hydroxy-ZO-spirox-S-ene is brominated to provide3B-hydroxy-S,6-dibromo-20-spiroxane. Bromination is convenientlyaccomplished by adding a solution of bromine in a halogenated hydrocarbon solvent, preferabl solution of 3,8-hydroxy-20-spirox-5-ene in thesame solvent, the solution being cooled and kept under nitrogen duringthe addition. After addition is complete, the solution is allowed tostand for about 15 minutes at about 5 C. and then concentrated byremoving the solvent under reduced pressure. The residual syrup isdissolved in acetone and upon cooling the acetone solution and allowingit to stand, crystalline 3B-hydroxy-5,6-dibromo-20-spiroxaneprecipitates. The precipitate is removed by filtration, washed with coldwater, and dried under reduced pressure.

3B-hydroxy-S,6-dibromo-20-spiroxane is used as the starting compound inthe preparation of 3-(4,6-androstadien-17fl-ol-3-one-17a-yl)-propionicacid lactone by a process which comprises a first step of oxidation toprovide 3-(5,6-dibromoandrostane-17/3-0l-3-one-17a-yl)-propionic acidlactone. Oxidation is accomplished by use of N-bromosuccinimide as anoxidizing agent. N-bromosuccinimide is added to a solution of3B-hydroxy-5,6-dibromo- 20-spiroxane in an inert organic solvent,preferably a solvent mixture composed of an aliphatic alcohol such astertiary butanol, water, and pyridine. The reaction mixture is stirredat room temperature for about 25 hours and then poured into cold water.The reaction product precipitates and is removed by extraction with asuitable organic solvent, such as methylenechloride. The extract iswashed AVAILABLE cop.

with water and dried over anhydrous magnesium sulfate. The reactionproduct, 3-(5,6-dibromo-androstane-175-01- 3-one-l7ot-yl)-propionic acidlactone, is present in the methylenechloride solution.

3-(4,6-androstadien-l7B-ol-3-one-l7tx-yl)-propionic acid lactone isprepared in the second step of the process by dehydrobromination of the3-(5,6-dibromoandrostane- 17 8-01-3-one-l7a-yl)-propionic acid lactone.Dehydrobromination is conveniently accomplished by treating the lattercompound with lithium carbonate, lithium bromide and anhydrousdimethylformamide. The lithium carbonate, lithium bromide and anhydrousdimethylformamide are added to the solution of3-(5,6-dibromoandrostanel7li-ol-3-one-l7a-yl) -propionic acid lactoneobtained from the first reaction step. After the reagents have beenadded, the solvent is removed by distillation under reduced pressure andthe residual reaction mixture is heated under nitrogen for about 18hours at a temperature offrom about 90 to 95 C. After the healingperiod, the reaction mixture is cooled to room temperature and pouredinto water. The reaction product is conveniently isolated by extractionwith a suitable solvent, such as ether, drying the extract overanhydrous magnesium sulfate, filtering, and removing the solvent bydistillation under reduced pressure. The residue is crude3-(4,6-androstadien-17 3-01- 3-one-17a-yl)-propionic acid lactone. Thecrude product may be purified by chromatography. Silica gel may be usedin the chromatographic procedure. A benzene solution of the crudeproduct is put on a column of silica gel and the purified product isrecovered by elution of the column with a suitable organic solvent, suchas benzene containing about 1% by volume of ethyl acetate.

PREPARATION 1.1 7a- 3'-HYDROXYPROPYL) -ANDROSTENE-3/3,17fi-DIOL 8.9grams of 3-chloropropanol-l,2'-tetrahydropyranyl ether is added over aperiod of 2 hours to a slurry comprising 0.8 gram of finely dividedlithium in 40 ml. of anhydrous ether. The temperature of the reactionmixture is kept under an argon atmosphere and maintained at 5 to 10 C.during the addition. The reaction mixture is filtered in an argonatmosphere to remove traces of unreacted lithium and lithium chloride.The clear filtrate is an ether solution of3-lithiopropanol-1,2-tetrahydropyranyl ether and is added to a solutionof 10.5 grams of dehydroepiandrosterone tetrahydropyranyl ether insolution in 110 ml. of anhydrous tetrahydrofuran over a period of 30minutes, during which time the temperature of the reaction mixture iskept below 30 C. The reaction mixture is allowed to stand for hours atroom temperature after addition is complete and is then cautiously addedto 500 ml. of cold water. This mixture is extracted three times withether and the combined ether extracts are washed with water and driedover anhydrous magnesium sulfate. The solvent is removed from the driedextracts by distillation under reduced pressure. The oily residue isl7a-(3'hydroxypropyl)-5-androstene-3 3,17fl-diol ditetrahydropyranylether.

PREPARATION 2 The oily residue from Preparation 1 is dissolved in 100ml. of ethanol and 0.7 gram of p-toluenesulfonic acid in solution in 10m1. of ethanol are added to the solution of the oily residue and theresulting solution is stirred at room temperature for 5 hours. Theprecipitate which forms is removed by filtration, washed with ethanol,and dried under reduced pressure. 5.66 grams of 17a-(3'-hydr0xypr0pyl)-5-androstene-3;3, l7 3-diol are obtained, which has amelting point of 274 to 278 C.

PREPARATION 3.3B-MESYLOXY-20-SPIROX- S-ENE 10.2 grams of mesylchlorideare added dropwise over a period of 20 to minutes to a slurry of 7.5grams of 17a-(3-hydroxypropyl)-5-androstene-3/i,17B-diol in 75 ml. ofanhydrous pyridine. The reaction mixture is kept at a temperature of 10C. during the addition. After addition is complete, the mixture isstirred for 3 hours and during this period the temperature is keptbetween -l0 C. and 0 C. The mixture is then allowed to come to roomtemperature and stand at room temperature overnight. After standingovernight, the reaction mixture is poured in 700 ml. of ice water, andthe precipitate is removed by extraction with ethyl acetate. The extractis washed with 0.5 N hydrochloric acid until free from pyridine, driedover anhydrous magnesium sulfate, and filtered. The solvent is removedby distillation under reduced pressure. A residue of 8.9 fine grams ofcrude 3 fl-mesyloxy-20-spirox-5 -ene is obtained, which has a meltingpoint of 132 to 134 C.

PREPARATION 4.3B-HYDROXY-20-SPIROX- 5-ENE The crude3/3-mesyloxy-20-spirox-S-ene is dissolved in a solvent mixture composedof ml. of acetone and 40 ml. of water. The resulting solution isrefluxed for 4 hours and the acetone is then removed by distillationunder reduced pressure and replaced simultaneously with water at a ratesuch that the volume in the distillation flask is maintained at aconstant level. The resulting slurry is cooled to 10 C., and the solidmaterial is removed by filtration, washed with water until acid free,and dried under reduced pressure. 7.1 grams of 3 3-hydroxy-20-spirox-S-ene are obtained, which has a melting point of 165 to 172 C.The crude 3 S-hydroxy-Z0-spirox-5-ene is suspended in 70 ml. ofnormal-hexane, and the suspension is stirred for 2 hours at atemperature of 60 C. The suspension is cooled to room temperature,filtered, and the solid material is washed with normal-hexane and driedunder reduced pressure. 670 grams of 3fi-hydroxy- 20-spirox-5-ene areobtained, which has a melting point of to 187 C.

PREPARATION 53fl-HYDROXY-5, G-DIBROMO- ZO-SPIROXANE 9.9 grams of 3S-hydroxy-20-spirox-S-ene are dissolved in 220 ml. of methylenechloride.The solution is cooled to 5 C. under nitrogen and a solution of 4.8grams of bromine and 25 ml. of 'methylenechloride is added over a periodof 10 minutes. After addition is complete, the solution is allowed tostand at a temperature of 5 C. for 15 minutes and the solvents are thenremoved by distillation under reduced pressure. The residue is dissolvedin 30 ml. of dry acetone and the acetone solution is cooled to 0 C. andallowed to stand at that temperature for 20 minutes. 3B-hydroxy-5,6-dibromo-20-spiroxane crystallizes from the acetone solution onstanding and is removed by filteration, washed with cold acetone, anddried under reduced pressure. 12.5 grams of 3fi-hydroxy-5,6-di'bromo-20-spiroxane, having a melting point of 124 to 125 C., areobtained.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are givne forpurposes of illustration and not of limitation.

Example 1 3- (5,S-DIBROMOANDROSTANE-17B-OL-3-ONE-l7a-YL) PROPIONIC ACIDLACTONE 2.2 grams of N-bromosuccinirnide are added to a solution of 1gram of 3fi-hydroxy-5, 6-dibromo-20-spiroxane in a solvent'mixturecomposed of 20 ml. of tertiary butanol, 1.2 ml. of water, and 1.2 ml. ofpyridine. The reaction mixture is stirred for 25 hours at roomtemperature and then poured into 100 ml. of cold water. The precipitatedproduct is removed by extraction with methylenechloride, the extract iswashed with water and dried over anhydrous magnesium sulfate.

3,413,289 6 Example 2 2. A process according to claim 1 in which in the0.6 gram of lithium carbonate, 0.55 gram of lithium bromide, and 6 ml.of anhydrous dimethylformamide are added to the methylenechloridesolution of 3-(5,6-dibromoandrostane-l'lfi-ol-El-one-l7u-yl)-propionicacid lactone obtained from Example I. The methylenechloride is removeredfrom the extraction mixture by distillation under reduced pressure, andthe residual reaction mixture is heated under nitrogen for 18 hours at90 to 95 C. After the heating period, the reaction mixture is cooled toroom temperature and poured into 100 ml. of water. The precipitatedproduct is removed by extraction with ether, and the ether extract isdried over anhydrous magnesium sulfate, and filtered. The ether isremoved by distillation under reduced pressure. The residue of crude3-(4,6-androstadien-1718-01-3-one-17a-yl)proprionic iacid lactone isdissolved in 50 ml. of benzene. The benezene solution is poured onto asilica gel column. 3-(4,6-androstadien-17p3-ol-3-one-17u-y1)-propionicacid lactone is removed from. the column 'by elution with benezencontaining 1% by volume of ethyl acetate and the solvent is removed fromthe eluate by distillation under reduced pressure. The purified producthas a melting point of 148 to 150 C.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of our invention.

What is claimed is:

1. A process for the preparation of3-(4,6-androstadienl7fl-ol-3-one-17a-y1)-propionic acid lactone whichcomprises the steps of oxidizing 3fl-hydroxy-5, 6-dibromo- ZO-spiroxanein solution in an inert organic solvent with N-bromosuccinimide toprovide 3-(5, 6-dibromoandrostane-17fl-ol-3-one-17a-yl)-propionic acidlactone and dehydrobrominating the latter compound by adding lithiumcarbonate and lithium bromide in dimethylformamide solution to asolution thereof in an inert organic solvent, removing the solvent bydistillation and heating the resulting mixture.

oxidation step the inert organic solvent is a mixture of an aliphaticalcohol, water and pyridine.

3. A process according to claim 1 in which the dehydrobromination stepis accomplished by heating the reaction mixture containing3-(5,6-dibromoandrostane- 17fi-ol-3-one-17a-yl)-propionic acid lactone,lithium carbonate, lithium bromide and dimethylforrnamide under nitrogenfor about 18 hours at a temperature of from to C., after the solvent hasbeen removed.

4. A process for the preparation of3-(5,6dibromanrotane-17/3-ol-3-one-17a-yl)-propionic acid lactone whichcomprises dehaydrobrominating 3-(5,6-dibromoandrosane in solution in aninert organic solvent with N-bromosuccinimide.

5. A process according to claim 4 in which the inert organic solvent isa mixture of an aliphatic alcohol, water and pyridine.

6. A process for the preparation of3-(4,6-androstadien-17fl-ol-3-one-17a-yl)-propionic acid lactone whichcomprises dehydrobrominating3-(5,6-dibromoandrostane-l7B-ol-3-one-17a-yl)-propionic acid lactone byadding lithium carbonate and lithium bromide in dimethylformamidesuspension to a solution thereof in an inert organic solvent, removingthe solvent by distillation and heating the resulting mixture.

7. A process according to claim 6 in which the reaction mixture whichremains after the solvent is removed by distillation is heated undernitrogen for about 18 hours at a temperature of from about 90 to 95 C 8.3-(5,6-dibromoandrostane-17,9-o1-3-one 17 31])- propionic acid lactone.

References Cited UNITED STATES PATENTS 2,900,383 8/1959 Ce1la 260239.573,074,936 1/1963 Zderic et al. 260239.57 3,280,116 10/1966 Webber260239.57

LEWIS GOTTS, Primary Examiner.

E. LOVE, Assistant Examiner.

